Method for preventing nasolacrimal duct obstruction

ABSTRACT

The invention is directed to a method for preventing nasolacrimal duct obstruction (NLDO) in a patient receiving high dose radioactive iodine for treatment of cancer. The method includes administering an effective amount of perchlorate anion to the eyes of the patient.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/925,260, which was filed Mar. 19, 2018 and a divisional applicationfrom U.S. patent application Ser. No. 15/099,034, which was filed Apr.14, 2016, issued as U.S. Pat. No. 9,962,332 on May 8, 2018, and was acontinuation of U.S. patent application Ser. No. 14/225,087, which wasfiled Mar. 25, 2014, issued as U.S. Pat. No. 9,314,426 on Apr. 19, 2016,and was a continuation of U.S. patent application Ser. No. 13/962,509,which was filed Aug. 8, 2013, issued as U.S. Pat. No. 8,722,012 on May13, 2014, and was a continuation of U.S. patent application Ser. No.12/012,469, which was filed Feb. 4, 2008, issued as U.S. Pat. No.8,529,871 on Sep. 10, 2013, and was a continuation of U.S. patentapplication Ser. No. 11/112,553, which was filed Apr. 25, 2005, andissued as U.S. Pat. No. 9,452,133 on Sep. 27, 2016, all of which areincorporated herein by reference as if fully set forth.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates the prevention of radiation injury to tissuesexpressing the protein sodium/iodide symporter (NIS) and especially toradiation injury to the lacrimal sac and nasolacrimal duct in cancerpatients being treated with high dose radioactive iodine.

Description of the Related Art

The sodium-iodide symporter is an integral membrane protein that residesin the basolateral membrane of epithelial cells located in such organsas the thyroid. The sodium-iodide symporter cannot distinguish betweennormal and radioactive iodide, thus providing a useful exploit fordiagnosis and treatment of certain thyroid disease. Small amounts ofradioactive iodine (I¹²³) injected into patients are rapidlyconcentrated in the thyroid, providing a means to image the thyroid fordetection of tumors and other abnormalities. Administration ofradioiodine (I¹³¹) is widely used for treatment of hyperthyroidism andsome types of thyroid cancer; in this case the radioactivity isconcentrated rather precisely in the tissue requiring destruction.

The sodium-iodide symporter simultaneously transports both Na+ and I−ions from extracellular fluid (i.e., blood) into the thyroid epithelialcell. This process is an example of secondary active transport. Energyis provided by the electrochemical gradient of sodium across the cellmembrane; the low intracellular concentration of sodium is maintained bysodium pumps. Although, the sodium-iodide symporter is most highlyexpressed in thyroid epithelial cells, lower levels of expression can bedetected in mammary gland, salivary gland, stomach, and colon tissue.See U.S. Pat. No. 6,803,199, columns 1 and 2.

Ophthalmic complications following I¹³¹ radiation therapy have beenobserved in a significant percentage of patients being treated forthyroid cancer. Symptoms such as ocular dryness, epiphora (watering ofthe eyes due to obstruction of the lacrimal passages), dry mouth(xerostomia), and nasolacrimal duct obstruction (NLDO) have beenobserved. Kloos et al., J. Clin. Endocrinol. Metab. 2002 December;87(12): 5817-20 and Burns et al., Opthal. Plast. Reconstr. Surg. 2004March; 20 (2):126-9.

It is believed that the cases of NLDO observed in some patientsreceiving high dose radioiodine treatment is due to the concentration ofradioactivity by the sodium-iodide symporter. High levels ofradioactivity concentrated by NIS in a relatively small area in thelacrimal sac and nasolacrimal duct causes fibrosis which results inblockage in the lacrimal duct and nasolacrimal sac. It is also believedthat some cases of dry mouth observed in patients being treated withhigh does radioiodine for head and neck cancers is due to accumulationof radioactivity in the salivary glands leading to fibrosis which blocksrelease of the salivary fluids.

The incidence of newly diagnosed head and neck cancers (excluding skincancers) in the U.S. is estimated at more than 50,000 cases annually.The most common type of cancer in the head and neck is squamous cellcarcinoma, which arises in the cells that line the inside of the nose,mouth, and throat. Other less common types of head and neck cancersinclude salivary gland tumors, lymphomas and sarcomas. In addition tohead and neck cancers, there are over 15,000 new cases of thyroid cancereach year in the United States.

Thyroid cancer is typically treated with surgery followed by radiationtherapy. The three main types of treatment for managing head and neckcancer are radiation therapy, surgery, and chemotherapy with the primarytreatment being radiation therapy or surgery, or both combined.

In addition to being used in the treatment of head and neck and thyroidcancers, radioactive iodine (I¹³¹) is widely used to treathyperthyroidism. Hyperthyroidism results from excess quantities ofthyroid hormone within the body. Rather than being classified as aspecific disease, it is classified as a syndrome that describes thecharacteristics resulting from this condition. The causes ofhyperthyroidism include Graves' disease; tumors of the thyroid gland,pituitary gland, testes or ovaries; inflammation of the thyroid from aviral infection or other inflammation; ingestion of excessive amounts ofthyroid hormone; and ingestion of excessive iodine. Graves' diseaseaccounts for 85% of all cases of hyperthyroidism. The incidence is 1 outof 1,000 people.

Finally, doctors are increasingly using radioiodine to treat breastcancer. Radioactive I¹³¹ is given either orally or by injection. UsingI¹³¹, the clinician is able to selectively target the cancerous breasttissue as opposed to normal breast tissue.

In the United States each year, as many as 100,000 people may be treatedwith high dose I¹³¹. This number is expected to increase as the use ofI¹³¹ to treat breast cancer becomes more common. With the increased useof high dose radioiodine, it is expected that the incidence of NLDO willincrease as well.

The traditional procedure most often relied on for relief of NLDO isincisional dacryocystorhinostomy (DCR). This procedure has a number ofdrawbacks: recovery time is significant, an incisional scar may developdue to invasive procedures, there is potential for excess bleeding, theprocedure must be done under anesthesia (usually general anesthesia),and the costs associated with the surgical procedure are not trivial.The DCR procedure has a high success rate in patients suffering fromNLDO caused by other than high dose radioiodine; however, in patientswhere the nasolacrimal duct is obstructed as a result of receiving highdose radioiodine, the DCR procedure does not work very well.

Currently, there is not available a safe and effective method forpreventing the fibrosis that can occur in the nasolacrimal duct area dueto the administration of high dose radioiodine. A method that preventsor reduces the formation of fibrosis in the nasolacrimal duct ratherthan treats fibrosis after it forms, is highly desirable. The method ofthe invention described herein avoids all of the drawbacks associatedwith DCR. It is a cost effective, safe, non-invasive method thatutilizes topical application of perchlorate anion in ophthalmicsolutions, ophthalmic creams, or gels to block the ability of thesodium-iodide symporter to concentrate radioactivity. The method of theinvention is so safe and effective and cost effective that it should bethe standard of care for every patient receiving high dose I¹³¹ therapyfor treatment of cancer and especially for treatment of head and neck,thyroid, and breast cancers.

SUMMARY OF THE INVENTION

The invention is directed to a method for preventing nasolacrimal ductobstruction (NLDO) in a patient receiving high dose radioactive iodinefor treatment of cancer, especially for treatment of thyroid, head andneck, and breast cancers which comprises administering to the eyes ofsaid patient an effective amount of perchlorate anion.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a simplified representation of the nasolacrimal systemanatomy. Tears are produced in the lacrimal gland 1, flow through ducts2 leading to the surface of the eyeball 3 and spread over the surface ofthe eyeball 3. When one blinks, the upper and lower eyelids 4 and 5,push the tears, which also contain proteins and sugars, to the insidecorner of the eye. There are two openings at the inside corner of eacheye near the nose 13, the superior puncta 6 and inferior puncta 7, whichopen into the vertical caniculi. The vertical caniculi bend at rightangles at the superior ampulla 8 and inferior ampulla 9 and form thehorizontal caniculi 10. The horizontal caniculi 10 drain tears and otherfluids into the lacrimal sac 11 which is connected with the nasolacrimalduct 12 and which opens into the nose 13.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a method for preventing nasolacrimal ductobstruction (NLDO) in a patient receiving radioactive iodine andespecially high dose radioactive iodine for treatment of cancer whichcomprises administering to each eye of said patient an effective amountof perchlorate anion.

A further embodiment of the invention is directed to a method forpreventing nasolacrimal duct obstruction (NLDO) in a patient receivinghigh dose radioactive iodine (I¹³¹) treatment for thyroid, head and neckand breast cancer which comprises administering to each eye of saidpatient an effective amount of perchlorate anion, wherein the patient ispre-treated with perchlorate anion for a period of from about 3 to about5 days prior to initiation of high dose I¹³¹ therapy, wherein treatmentwith perchlorate anion continues for as long as the patient receiveshigh dose radiation therapy, and wherein treatment with perchlorateanion is continued for from about 3 to about 5 days after cessation ofradiation therapy.

The term “nasolacrimal duct obstruction” (NLDO) as used herein to referto a blockage in the distal horizontal caniculi 10, lacrimal sac 11and/or the nasolacrimal duct 12 which prevents liquid from draining intothe nose. As a result of the blockage there is a buildup of tears,containing mucin, sugars, and other components such as bacteria in theareas just described leading to irritation and infection.

Symptoms of NLDO are epiphora (excessive tearing) due to a decrease intear draining, inflammation and infection (dacryocystitis) of thelacrimal sac. The area beneath the eyes next to the nose can become red,inflamed, and sensitive to the touch. The area usually is swollen, andthere may be a mucous discharge from the opening of the nasal corner ofthe eye. Common complaints include itching, irritation, burning,redness, conjunctivitis, and pain.

As used herein, the term “high dose” radioactive iodine (RAI) refers tocumulative doses of radioactive iodine (I¹³¹) of about 150 mCi orgreater. Although iodine can be made into two radioactive isotopes formedical uses, I¹²³ and I¹³¹, the radiation that I¹²³ gives off isgenerally used in scanning or imaging rather than for treatment. The RAIthat is most often used in chemotherapy is I¹³¹. It is usuallyadministered to the patient by mouth either as a capsule or a liquid orintravenously (IV). RAI that is not concentrated in tissue is eliminatedfrom the body through sweat and urine.

The term “perchlorate anion (CIO4−)” as used herein refers to the anionwhich is produced when solid salts of ammonium, potassium, and sodiumperchlorate, and perchloric acid are dissolved in an aqueous liquid.

The term “effective amount” is used herein to mean an amount ofperchlorate anion sufficient to reduce or inhibit fibrosis in the distalcaniculi, lacrimal sac and/or nasolacrimal duct caused by theconcentration of radioactivity by the NIS protein in a patient receivingradioiodine therapy. Any source of perchlorate ion may be used in themethod of the invention. However, potassium perchlorate and sodiumperchlorate are preferred for use in the methods of the inventionbecause they are in use in other approved pharmaceutical applicationsand pharmaceutical grade (USP) compound is readily available.Administration of perchlorate anion to the patient should be startedfrom about 3 to 5 days prior to the initiation of I¹³¹ chemotherapy andshould continue during the course of chemotherapy and for 3 to 5 daysafter cessation of I¹³¹ therapy.

Preferred for use in the method of the invention are ophthalmicmedicaments containing from about 10 mg/ml to about 500 mg/ml ofpotassium perchlorate (KCIO₄) or sodium perchlorate (NaCIO₄) andpreferably from about 40 mg/ml to about 400 mg/ml and more preferablyfrom about 50 mg/ml to from about 100 mg/ml.

The ophthalmic medicament containing the perchlorate anion is topicallyadministered in the corner of the eye near the superior and inferiorpuncta 6 and 7. The perchlorate anion may be administered topically tothe eye as for example a sterile liquid, e.g., an eye wash or eye drops,an aqueous gel, or ophthalmic ointment or cream. As would be recognizedby one skilled in this art, any ophthalmic formulation that is sterileand that is pharmaceutically acceptable, i.e., is safe and effective forits intended purpose may be used to deliver perchlorate anion to thelacrimal sac and nasolacrimal duct.

The maximum volume of the lacrimal sac is about 30 μl. The averagevolume of a human tear is 7 μl. Most commercially eye drops have a perdrop volume in the range of from 50-75 μl. If the droplet volume is muchexcess of 75 μl it probably will not get into the lacrimal sac and thus,the nasolacrimal duct, and the excess solution will be wasted as itdrips out of the eye and down the face. Ideally, an eye drop solutionwill have a high concentration of drug in a minimum drop volume.Multiple drops administered at intervals, produces higher drugconcentrations in the lacrimal sac and nasolacrimal duct.

An alternative to a solution of perchlorate anion for use in the methodsof the invention is an ophthalmic ointment containing the perchlorateanion. An advantage of an ointment is that it has a longer contact timewith the eye and potentially greater total drug bioavailability. Sincean ointment can interfere with vision it is best used at bedtime. Theperchlorate is added to the ointment base as a solution or a micronizedpowder. Most ophthalmic ointments are prepared with a base of whitepetrolatum and mineral oil, often with anhydrous lanolin. Some contain apolyethylene-mineral oil gel. Whatever base is used, it must benonirritating to the eye, permit diffusion of the drug throughout theeye and retain activity of the perchlorate for a reasonable period oftime upon storage.

The ophthalmic medicament containing perchlorate anion may beself-administered or it may be administered by the clinician, in whichcase it may be instilled directly into the lacrimal sac and nasolacrimalduct.

As would be recognized by one skilled in this art, it is within theskill of the art to prepare sterile, shelf-stable ophthalmic solutions,gels and ointments. See for example, Remington's Pharmaceutical Sciences18th Ed., Alfonso Gennaro Editor, 1990, Mack Publishing C., Easton, PA18042, pp. 1581-1595 (now known as Remington: The Science and Practiceof Pharmacy, 20th Edition, Alfonso Gennaro Editor, Lippincott Williams &Wilkins, Baltimore, MD) for information regarding the properties of, andthe preparation of, ophthalmic solutions and ointments.

Both potassium perchlorate and sodium perchlorate are in use to minimizeor reduce accumulation of technetium or I¹²³ in certain tissues inpatients undergoing imaging studies. Potassium perchlorate is availablefrom Mallinckrodt Inc., St. Louis, MO. 63134 under the trade namePerchloracap®. Perchloracap is supplied for use during diagnosticstudies as an opaque gray gelatin capsule for oral administration. Eachcapsule contains 200 milligrams of potassium perchlorate (KCIO4) mixedwith an inert filler. Perchloracap is administered to minimize theaccumulation of pertechnetate Tc 99m in the choroid plexus and in thesalivary and thyroid glands in patients receiving sodium pertechnetateTc 99m injection for brain and blood pool imaging and placentalocalization.

Sodium perchlorate is manufactured in the United Kingdom by Torbay PMU,a division of the South Devon Healthcare Trust and is available in theU.K. as a 20 mg/ml solution for injection. Sodium Perchlorate Injectionis used as a thyroid blocking agent for patients unable to toleratealternative oral thyroid blocking agents when undergoing studies withradioiodinated radiopharmaceuticals known to de-iodinate in vivo.

Although potassium and sodium perchlorate have been used to blockaccumulation of technetium 99m and I¹²³ in the thyroid gland, choroidplexus, and salivary glands there is no recognition in the art thatperchlorate may reduce or eliminate fibrosis that can occur in thenasolacrimal area in patients receiving high dose radioiodine fortreatment of various cancers.

The invention and the manner and process of making and using it are nowdescribed in such full, clear, and concise terms as to enable any personskilled in the art to which it pertains to make and use same. It is tobe understood that the forgoing describes preferred embodiments of thepresent invention and that modifications may be made therein withoutdeparting from the spirit or scope of the present invention as set forthin the claims. To particularly point out and distinctly claim thesubject matter regarded as the invention, the following claims concludethis specification.

What is claimed is:
 1. A method for reducing formation of fibrosis in atleast one nasolacrimal duct of a patient that may occur upon the patientreceiving radioactive iodine, the method comprising administering to thepatient by topically delivering an ophthalmic composition comprisingperchlorate anion to at least one eye of the patient, or instilling theophthalmic composition directly into the at least one nasolacrimal ductor at least one lacrimal sac of the patient, wherein the perchlorateanion is at a concentration of about 40 mg/ml to about 400 mg/ml and theophthalmic composition further comprises at least one of whitepetrolatum, mineral oil, lanolin, or polyethylene mineral oil gel. 2.The method of claim 1, wherein the radioactive iodine is high dose I¹¹³.3. The method of claim 1, wherein the patient receiving radioactiveiodine is receiving the radioactive iodine for treatment of cancer. 4.The method of claim 3, wherein the cancer is head and neck cancer,thyroid cancer, or breast cancer.
 5. The method according to claim 1,wherein the patient receiving radioactive iodine is receiving theradioactive iodine to treat a condition selected from the groupconsisting of Grave's disease, tumor of the pituitary gland, tumor ofthe testes, tumor of the ovaries, inflammation of the thyroid, andingestion of excessive amounts of thyroid hormone.
 6. The method ofclaim 1, wherein the patient receiving radioactive iodine is receivingthe radioactive iodine for treatment of hyperthyroidism.
 7. The methodof claim 1, wherein the ophthalmic composition consists essentially ofthe perchlorate anion and the at least one of white petrolatum, mineraloil, lanolin, or polyethylene mineral oil gel.